Description: Deregulated Wnt signaling has been observed in a number of human cancers. Even though increased levels of nuclear beta-catenin have been observed in aggressive forms of human prostate cancer and are very good evidence of an activated canonical Wnt signaling pathway, no direct or causal relationship between deregulation of the Wnt signaling axis and initiation, progression, metastasis or development of androgen depletion independent (ADI) disease has been demonstrated. The research outlined in this proposal will test the central hypothesis that deregulated Wnt signaling can indeed cause prostate cancer through three interrelated specific aims: 1) determine the consequence of enforced expression of the proto-oncogene, Wnt3, on epithelial cells of the mouse prostate, 2) determine the consequence of enforced Wnt3 expression during tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model and 3) determine the influence of Wnt signaling on tumor growth and differentiation in an allograft model using prostate cancer derived cell lines engineered to express high levels Wnt3. The long-term objectives of this research will increase our understanding of how Wnt signaling contributes to prostate cancer, examine the role that deregulated Wnt signaling plays in deadly bone metastases and facilitate development of new treatment strategies. Relevance to Public Health: The research outlined in this proposal has direct relevance to a major public health concern, prostate cancer. The work will exploit genetically engineered mouse models to expand current understanding of the role that activation of the Wnt/beta-catenin pathway plays in prostate biology and cancer. PHS 416-1 (Rev.10/05) Page 2 Number pages consecutively at the bottom throughout Form Page 2 NAME OFAPPLICANT (Last, first, middle initial) Kirschstein-NRSA Individual Fellowship Application Houghtaling, Scott R (To be completed byapplicant - follow PHS 416-1 instructions) 20. GOALS FOR KIRSCHSTEIN-NRSA FELLOWSHIP TRAINING AND CAREER My experience as an undergraduate student exposed me to the tool set available to explore fundamental questions of biology. I became convinced of my desire to pursue science as a career during my graduate research experience in the laboratory of Dr. Markus Grompe. The exposure to a variety of research areas including stem cell biology and cancer genetics in the Grompe lab, fueled my appreciation for the complexity of human disease and underscored a belief that laboratory research can lead to improved treatment and diminished suffering associated with disease. I've carriedthis belief into my postdoctoral research experience in the lab of Dr. Norman Greenberg. Dr. Greenberg is a leader in developing mouse models of human prostate cancer. In applying a genetically engineered mouse (GEM) model of human prostate cancer to preclinical testing of novel therapies, Dr. Greenberg has also developed a strong interest in imaging tumors in mice. He has surrounded himself with the research facilities required to pursue his interests in imaging, (continued on page 4) 21. ACTIVITIES PLANNED UNDER THIS AWARD: instructions.) Year Research First 100% Second 100% Third 100% Fourth Fifth Approximate percentage of proposed award time in activities identified below. (See Course Work Teaching Clinical PREDOCTORAL FELLOWSHIPS ONLY MD/PhD FELLOWSHIPS ONLY Sixth Briefly explain activities other than research and relate them to the proposed research training. 22. TRAINING SITE(S) (organization, city, state) Fred Hutchinson Cancer Research Center 1100 Fairview Avenue N Seattle, WA 98109 23. HUMAN EMBRYONIC STEM CELLS Kl No D Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.gov/reqistrv/index.asp. Usecontinuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line PHS41R-1 Pane 3 Fnrm Pane 3 Name ofApplicant (Last, First, Middle): Houghtaling, Scott R 20. GOALS FOR KIRSCHSTEIN-NRSA FELLOWSHIP TRAINING AND CAREER (continued from page 3) The first goal of my postdoctoral research experience is to investigate the role that deregulated stem cell self- renewal pathways have in development of prostate cancer and deadly bone metastases. During completion of this goal, I expect to gain experience in the generation of transgenic mouse lines. I hope to develop skills in transgene construction, animal husbandry, and phenotypic analysis through observation, dissection, tissue fixation, histology preparation and microscopic evaluation. In working with resident patholbgists, I will learn how to extract observations from histology samples and develop these observations into appropriate conclusions. A second goal of rriy postdoctoral research is to develop an understanding of the signaling events that are often deregulated in human cancers. Finally, the ultimate goal of my postdoctoral experience is to develop the necessary skills in laboratory research, particularly the design and application of GEM models of cancer, that will allow me to continue on the career trajectory of directing my own research team as an independent investigator. PHS 416-1/416-9 (Rev.10/05) Page 4 . Continuation Format Page Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Table of Contents Houghtaling, Scott R Page Numbers (Number pages consecutively at the bottom throughout the application. Section 1 - Applicant Do not use suffixes such as6a,6b.) Face Page.... 1 Sponsor's Contact Information, Description (Form Page 2) 2 Training &Career Goals, Activities Planned Under This Award, Training Site, Human Embryonic Stem Cells (Form Page 3) 3 Table of Contents (Form Page 4) 5 Biographical Sketch - Applicant/Fellow (Not toexceed four pages) 6-8 Previous Research Experience (Form Page 5) 9-10 Research Training Plan Introduction to Revised Application (not to exceed 1page) 11 A. Specific Aims .-x / 12 B. Background/Significance r.....(A/of toexceed 10 pages) I 13-15 C. Preliminary Studies/Progress Report.../" | 15-16 D. Research Design andMethods ,J ^ 16-20 E. Human Subjects (Requiredif Item 9 on the Face Page is marked "Yes") n/a Protection of Human Subjects (Required if Item 9 on the Face Page is marked "Yes") n/a Data and Safety Monitoring Plan (Required if Item 9 on the Face Page is marked "Yes" and a Phase I, II, or III clinical trial is proposed n/a Inclusion of Women and Minorities (Required if Item 9 on the Face Page is marked "Yes" and is Clinical Research) n/a Targeted/Planned Enrollment Table (for new and continuing clinical research studies) n/a Inclusion of Children (Required if Item 9 on the Face Page is marked "Yes") n/a F. Vertebrate Animals (Requiredif Item 10on the Face Page is marked "Yes") 20 G. Literature Cited 20-22 H. Resource Sharing 22 I. Respective Contributions 23 J. Selection of Sponsor and Institution 23 K. Responsible Conduct of Research 23-24 Section 2 - Sponsor's/Co-Sponsor's Information Biographical Sketch-Sponsor 25-27 Research Support Available 28 Previous Trainees 28 Training Plan, Environment, Research Facilities 28-29 Number of Fellows/Trainees to be Supervised 29 Applicant's Qualifications and Potential 29-30 Checklist (Completed by Fellow/Applicant &Sponsoring Institution) 31 Section 3 - References (Minimum of 3) (See instructions for submission of references.) List full name, institution, and department of individuals submitting reference letters. Markus Grpmpe, M.D., Oregon Health &Science Univ, Dept of Medical Genetics Robb Moses, M.D., Oregon Health &Science Univ, Dept of Medical Genetics R. Michael Liskay, Ph.D., Oregon Health &Science Univ, Dept of Medical Genetics Other Items (list): Personal Data Page for Fellowship Applicants Section 4 - Appendix (5 collatedsets. Nopage numbering necessary. Not to exceed 3publications;2 for predoctoral candidates.) K Check if Appendix is included PHS41R-1 Panp fi Fnrm Pane A